A problem encountered by oncologists is that they must balance the benefit of chemotherapy against the risk of killing the patient during the course of killing their cancers. One of the life-threatening side effects of chemotherapy is that cytotoxic drugs kill cancer cells but also kill healthy cells and in particular kill the patients' stem cells. Stem cells in the bone marrow are constantly regenerating to supply the body with red blood cells, which carry oxygen, white blood cells, which fight infection and platelets which cause the blood to clot. Chemo and radiation can destroy the stem cells which eventually become blood cells and thus put the patient's life at risk, which makes the physician reduce the cancer killing treatments. The problem with designing agents to counter these deleterious effects of cancer treatment is that blood cells are terminally differentiated cells—meaning that they cannot divide to replicate themselves. They developed from hematopoietic stem cells in the bone marrow. This means that it is not possible to collect some red or white blood cells from a patient and expand them in vitro then inject them back into the patient.
There are currently a handful of drugs on the market that are used to modulate stem cell development in a patient. The first group, known as erythropoiesis stimulating agents (ESAs), includes Epoetin, marketed under the trade names Procrit and Epogen, and Aranesp. These drugs are used to treat anemia in patients with chronic kidney disease and in cancer patients with chemotherapy-induced anemia. These drugs do not stimulate the growth of stem cells in the bone marrow but rather skew the development of the patient's stem cells such that more become blood cells of the erythroid lineage. Epogen and epogen-like drugs help cancer patents and chronic kidney disease patients by increasing the number of stem cells in the bone marrow that differentiate into red blood cells.
Another class of drugs that is used to stimulate the production of white blood cells. Colony-stimulating factors (CSFs) that include G-CSF (granulocyte-colony stimulating factors: marketed as Filgrastim) and GM-CSF (granulocyte-macrophage colony stimulating factors: Sargamostim marketed as Leukine) stimulate the production of the precursors of white blood cells, which can mature to become neutrophils, macrophages and dendritic cells and may be administered with or without cyclophosphamide. The CSFs are also stem cell mobilizers which cause blood cell progenitors to be secreted from the bone marrow. However, a drawback of G-CSF and GM-CSF is that they inhibit bone formation. Another mobilizer of hematopoietic stem cells is the CXCR4 antagonist AMD3100, which reportedly mobilizes blood cell progenitors without inhibiting bone formation.
Both erythropoiesis stimulating agents (ESAs) and CSFs can be used to accelerate the recovery of blood cells from effects of chemotherapy, used after bone marrow transplant, used before or after stem cell transplant which may be transplanted into the peripheral blood, and or to treat a patient who could benefit from increased production of hematopoietic stem cells or blood cells or their progenitors.
Both ESAs and CSFs function by skewing the maturation of stem cells toward the hematopoietic stem cell lineages and necessarily away from maturation into other types of cells. It follows that there may be unwanted and dangerous side effects stemming from the inhibition of other types of cells that are produced in the bone marrow. In fact, the FDA recently issued warnings that the use of Procrit, Epogen or Aranesp increases the risk of developing cancers and also increases the risk of heart attack and stroke.
Thus an improvement would be the development of agents that stimulate the production of or skew the development of stem cells to blood cell lineages via a pathway that is different from that of the ESAs and the CSFs. A greater improvement to the state of the art would be the development of agents that stimulate the production of stem cells in the bone marrow rather than just skewing their maturation in one direction. An even greater improvement to the state of the art would be the development of an agent(s) that would stimulate the growth of stem cells but would not stimulate the growth of cancer cells or increase the patient's risk of developing another cancer. A yet greater improvement would be the development of an anti-cancer agent that would kill the cancer cells without killing the patient's stem cells.